1. Field of the Invention
This invention relates to certain novel acyltripeptides useful as antiinfective agents and immunomodulators for stimulation of host defenses in patients with an increased risk of bacterial infection, to intermediates therefor and to a process for making said acyltripeptides.
2. Description of the Prior Art
The relatively new field of immunopharmacology, and particularly that segment thereof which deals with immunomodulation, continues to develop at a rapid pace. A variety of naturally occurring compounds has been investigated, including the tetrapeptide tuftsin, known chemically as N.sup.2 -[1-(N.sup.2 -L-threonyl-L-lysyl)-L-prolyl]-L-arginine. Much attention has been directed to synthetic peptidoglycan derivatives, especially those known as muramyl dipeptides. For summaries of the wide range of compounds investigated as immunomodulators, and especially as immunostimulants, attention is directed to Dukar et al., Annu. Rep. Med. Chem., 14, 146-167 (1979), Lederer, J. Med. Chem., 23, 819-825 (1980) and to J. Kralovec, Drugs of the Future, 8, 615-638 (1983).
Immunostimulant peptides have been described in a number of patent specifications:
L-Alanyl-alpha-glutaric acid N-acyl dipeptides in German Pat. No. 3,024,355, published Jan. 15, 1981; PA0 tetra- and penta-peptides containing D-alanyl-L-glutamyl moieties or L-alanyl-D-glutamyl moieties in Brit. Pat. No. 2,053,231, published Feb. 4, 1981 and German Pat. No. 3,024,281, published Jan. 8, 1981, respectively; and PA0 N-acyl-L-alanyl-alpha-D-glutamyl tripeptide derivatives in which the C-terminal amino acid is lysine or diaminopimelic acid in Ger. Pat. No. 3,024,369, published Jan. 15, 1981; and PA0 lactyl tetrapeptides composed of N-lactylalanyl, glutamyl, diaminopimelyl and carboxymethylamino components in EP-11283, published May 28, 1980.
Further immunostimulant polypeptides having the formula (A) ##STR1## wherein R.sup.1 is hydrogen or acyl; R.sup.2 is inter alia hydrogen, lower alkyl, hydroxymethyl, benzyl; R.sup.3 and R.sup.4 are each hydrogen, carboxy, --CONR.sup.7 R.sup.8 wherein R.sup.7 is hydrogen, lower alkyl optionally substituted with hydroxy; and R.sup.8 is mono- or dicarboxy lower alkyl; R.sup.5 is hydrogen or carboxy with the proviso that when one of R.sup.4 and R.sup.5 is hydrogen, the other is carboxy or --CONR.sup.7 R.sup.8 ; R.sup.6 is hydrogen; m is 1 to 3 and n is 0 to 2, and derivatives thereof in which the carboxy and amino groups are protected are disclosed in U.S. Pat. Nos. 4,311,640 and 4,322,341; EP applications Nos. 25,482; 50,856; 51,812; 53,388; 55,846 and 57,419.
Kitaura et al., J. Med. Chem., 25, 335-337 (1982) report N.sup.2 -(gamma-D-glutamyl)-meso-2(L),2'(D)-diaminopinemic acid as the minimal structure capable of eliciting a biological response characteristic of the compound of formula (A) wherein n is 1; R.sup.1 is CH.sub.3 CH(OH)--CO--; R.sup.2 is CH.sub.3 ; each of R.sup.3 and R.sup.5 is --COOH; R.sup.4 is --CONHCH.sub.2 COOH; and R.sup.6 is H. Said compound of formula (A) is known as FK-156.